SUMMARY The unifying theme of this PPG renewal is understanding the pathophysiology, and thereby establishing the optimal management of two of the most frequently encountered hematologic conditions among critically ill, premature infants: anemia and thrombocytopenia. Current treatment for these conditions relies largely on transfusion of red blood cells and platelets, therapies that remain empiric, controversial and incompletely investigated in this population. Prior studies by our PPG group and others have established that many aspects of the pathophysiology of anemia and thrombocytopenia in premature infants are unique to this population. However, our understanding of the consequences of this unique physiology in informing various treatment strategies is incomplete. Importantly, studies from our group suggest that treatment approaches substantially influence short- and long-term outcomes. Hence, the goals of our renewal are to define the unique hematological features of preterm infants as they mature, the novel roles of red blood cells and platelets on neonatal inflammation and immune regulation, and the consequences of neonatal anemia and its two commonly utilized treatment strategies on neurodevelopment. Our 4 interrelated projects, whose objectives are directly relevant to our unifying theme, include: Project 1 ?Impact of thrombocytopenia and platelet transfusions on neonatal inflammation and host defense,? PL Martha Sola-Visner; Project 2 ?Impact of anemia on gut injury and immune function in preterm infants,? PL Cassandra Josephson (and Sean Stowell); Project 3 ?The effect of neonatal anemia and its treatment on brain development,? PL Michael Georgieff; and Project 4 ?The effect of anemia and its treatment on neurodevelopmental outcomes of premature infants,? PL Peg Nopoulos. Core A (?Administrative and data management core?) and Core B (?Biostatistical analysis and mathematical modeling core,?) will provide support for all projects. Our goals will be achieved through a combination of human clinical/translational studies and closely-matched animal models, in order to incorporate clinical and mechanistic insights to better understand the developmental stage-specific effects of cytopenias and transfusions in neonates. At our last renewal, and again in this submission, our PPG broke geographical barriers to pursue the best possible combination of multidisciplinary scientists to achieve our goals. Our history of success conducting multisite research will be invaluable in coordinating studies across the various performance sites. Over the past 24 years, our PPG has made a substantial impact on clinical practice and research in neonatal hematology and transfusion medicine. With this renewal, we are poised to continue to challenge paradigms and advance knowledge, with the ultimate goal of improving the outcomes of our most vulnerable patients.